Song Yohan, Xia Anping, Lee Hee Yoon, Wang Rosalie, Ricci Anthony J, Oghalai John S
Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California.
Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California
J Neurophysiol. 2015 Jun 1;113(10):3531-42. doi: 10.1152/jn.00869.2014. Epub 2015 Mar 25.
Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used Tecta(C1509G) mice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied Tecta(C1509G) mice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment.
Prestin是外毛细胞（OHC）电运动性和正常听力所必需的一种膜蛋白。其调节机制尚不清楚。几种听力损失的小鼠模型显示Prestin增加，这促使我们研究听力损失如何反馈到OHC上。为了测试中枢介导的反馈是否调节Prestin，我们开发了一种新型的内毛细胞损失模型。向成年CBA小鼠注射白喉毒素（DT）导致内毛细胞显著损失，而不影响OHC。因此，注射DT的小鼠失聪是因为尽管OHC继续接受正常的听觉机械刺激且功能正常，但它们没有传入听觉输入。膜片钳实验表明OHC的Prestin没有变化，这表明中枢信息传递的丧失并没有改变Prestin的表达。为了测试局部机械反馈是否调节Prestin，我们使用了Tecta（C1509G）小鼠，其盖膜畸形，只有一些OHC受到刺激。与盖膜相连的OHC的Prestin水平正常，而未与盖膜相连的OHC的Prestin水平升高，支持了一种活动依赖模型。为了测试内淋巴电位是否是Prestin调节所必需的，我们研究了不同发育年龄的Tecta（C1509G）小鼠。在出现内淋巴电位之前，未与盖膜相连的OHC的Prestin水平低于正常水平，而在出现内淋巴电位之后，其Prestin水平高于正常水平。综上所述，这些数据表明OHC的Prestin水平是通过需要机械电转导电流的局部反馈来调节的。这种适应性可能有助于补偿局部机械环境的变化。
